A previously unknown lignan, methyl-(7S, 8S)-4-hydroxy-4',7-epoxy-8,3'-neolignan-7'-ate (MEHN), was isolated from an extract prepared from the pooled stems and leaves of Conocarpus lancifolius and structurally elucidated using comprehensive spectroscopic analysis and ECD calculations. The compound revealed prominent antiradical activity in both ABTS (IC50 = 18.90 ± 1.85 µM) and DPPH (IC50 = 36.95 ± 2.47 µM) assays, relative to the reference antioxidant ascorbic acid. In an MTT colorimetric assay, MEHN at various concentrations (1.562-200 µM) exerted pronounced cytotoxic effects against HepG2 (IC50 = 14.30 ± 2.70 µM) and MCF-7 (IC50 = 20.81 ± 1.34 µM) cells, while showing weak cytotoxicity against HCT-116, H1299, H522, and non-malignant cell line MCF-10A (IC50 > 100 µM), indicating selective activity against specific cancer cell lines when compared with the standard chemotherapeutic agent 5-fluorouracil. Its computational ADMET evaluation showed favorable pharmacokinetic behavior, compliance with drug-likeness criteria, and low predicted toxicity. Overall, the newly isolated lignan sheds light on the chemical diversity of C. lancifolius with multifunctional biological activities, suggesting its potential relevance for further chemical and pharmacological research.

The genus Eugenia comprises approximately 1050 species widely used in traditional medicine and human nutrition due to their diverse pharmacological properties. This review aimed to critically summarize the anticancer potential of Eugenia species and to correlate their biological activities with the presence of bioactive phytochemicals. Literature published between 2013 and 2025 was retrieved from PubMed, SciELO, and Google Scholar databases using terms related to Eugenia, cancer, antiproliferative, and cytotoxic activities. Increasing evidence has demonstrated the anticancer effects of selected Eugenia species in in silico, in vitro, and in vivo models against different cancer types. These effects are associated with multiple mechanisms, including apoptosis induction via caspase-3/7 activation and Fas receptor upregulation, inhibition of tumor cell migration and invasion through suppression of MMP-2 and MMP-9, and cell cycle arrest. The observed activities are closely related to the presence of flavonoids, phenolic acids, carotenoids, monoterpenes, triterpenes, and sesquiterpenes. Despite promising preclinical findings, limitations such as the scarcity of in vivo studies, lack of extract standardization, and absence of clinical trials still hinder the translational application of Eugenia-derived compounds in oncology. Future studies focusing on mechanistic elucidation, bioavailability, toxicity, and clinical validation are essential for the development of Eugenia-based anticancer therapies.

Multiple myeloma (MM) is a hematological malignancy with limited therapeutic options. Drug repurposing offers a pragmatic strategy to identify novel candidates, including those from Traditional Chinese Medicine (TCM). Here, a gene signature-guided repurposing approach was applied to transcriptomic data using Limma and weighted gene coexpression network analysis to define MM-associated hub genes, followed by diagnostic and prognostic evaluation. Coremine Medical screening identified Camellia sinensis root (CSR) and Ginkgo biloba leaves (GBL) as promising candidates. CSR and GBL extracts inhibited MM cell proliferation with IC50 values of 1.54 mg/mL and 1.79 mg/mL, respectively, and induced G2/M cell cycle arrest with cyclin B1 downregulation. Apoptosis assays showed increased cell death and Bcl-2/Bax modulation. Wnt/β-catenin signaling was suppressed, correlating with cell cycle arrest and apoptosis. HPLC analysis revealed that CSR is rich in amino acids and flavanols, including L-theanine and epicatechin, while GBL contains flavonol glycosides and terpene lactones, such as quercetin, kaempferol, isorhamnetin, ginkgolide A-C, and bilobalide. These results indicate that CSR and GBL exert selective anti-myeloma activity via Wnt/β-catenin-mediated cell cycle arrest and apoptosis, highlighting their potential as repurposing candidates for MM.

The development of new therapeutic agents for glioblastoma and hepatocellular carcinoma (HCC) remains a priority due to poor prognosis, limited treatment options, and high recurrence rates. Herein, we report a one-pot synthesis of aromatic aminopropyl lactams (ArAPLs) via hydrolysis of bicyclic amidines (DBN, DBU), followed by reductive amination with aromatic aldehydes. These compounds were designed to target histamine H3 receptors (H3R), which are often overexpressed in these malignancies. Docking studies suggested that compounds 3a and 4a may act as H3R antagonists, showing favorable binding through hydrophobic and hydrogen-bonding interactions. Biological evaluation identified 3a and 4a as the most promising compounds, exhibiting micromolar antiproliferative activity in glioblastoma and HCC cell models. Compound 3a showed the best balance between potency and selectivity, including activity in 3D spheroid models and modulation of cell cycle-related markers. In coculture systems, spheroids displayed reduced size and density, although a slight increase in viability was observed, particularly with 4a. Variations in peripheral cell layers suggest a role for macrophage behavior. Overall, these findings support the cytotoxic potential of ArAPLs, although further studies are required to confirm their role as H3R antagonists.

Organotin (IV) compounds are known to induce apoptosis via the intrinsic mitochondrial pathway, which is a key mechanism of effective anticancer therapy. Their ability to selectively promote apoptotic cell death highlights their potential as chemotherapeutic agents. In this study, the in vitro effects of two triorganotin compounds, tributyltin propionate and tributyltin salicylate, on the human breast cancer cell line MDA-MB-231 were evaluated. In addition to their proven antitumor activity, these compounds may act as synthetic ligands for nuclear retinoid X receptors. Protein expression profiles were examined using gel electrophoresis and MALDI-TOF mass spectrometry, with a particular focus on heat shock proteins (HSPs), which are commonly overexpressed in cancer cells and contribute to tumor progression and therapeutic resistance. Both triorganotin derivatives significantly reduced HSP expression, suggesting that HSPs could be a promising target in cancer therapy.

The prognostic value of CT-detected tumor necrosis in advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitor (ICI) monotherapy remains unclear. This two-center retrospective study investigated whether tumor necrosis on pretreatment CT independently predicts overall survival (OS).

Claudin-14 (CLDN14) is a tight junction protein that contributes to the development of chemoresistant phenotypes in human colorectal cancer (CRC) cells. CLDN14 may represent a potential therapeutic target for CRC. In this study, we identified velpatasvir (VEL), a clinically approved hepatitis C virus nonstructural protein 5 A (NS5A) inhibitor, as a potent suppressor of CLDN14 protein expression using in silico screening and Western blot analysis. CLDN14 expression was not decreased by other NS5A inhibitors, including ledipasvir, pibrentasvir, and daclatasvir. Quartz crystal microbalance analysis revealed that VEL directly binds to recombinant CLDN14 protein with a dissociation constant of 1.8 ± 0.2 μM. VEL treatment did not affect CLDN14 mRNA levels, suggesting that CLDN14 expression is regulated at a post-transcriptional level. Pharmacological inhibition of clathrin-mediated endocytosis and lysosomal degradation significantly reversed the VEL-induced reduction in CLDN14 protein levels, suggesting the involvement of endocytosis-lysosomal degradation pathway. Functionally, VEL increased paracellular permeability to mineral ions and enhanced the transepithelial flux of aqueous fluorescent tracers. In DLD-1 spheroids, VEL attenuated intracellular oxidative stress and reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), a central regulator of redox homeostasis. Consequently, VEL promoted the intracellular accumulation of doxorubicin and significantly potentiated its cytotoxic effects. Moreover, VEL enhanced the antitumor efficacy of other chemotherapeutic agents, including oxaliplatin and SN-38, the active metabolite of irinotecan. These findings suggest that VEL enhances anticancer drug sensitivity in CRC cells through lysosome-dependent downregulation of CLDN14 protein and suppression of Nrf2-dependent oxidative stress responses.

Chemotherapy resistance remains a major clinical challenge in the treatment of gastrointestinal (GI) cancers. Mitochondrial remodeling contributes to chemoresistance through several interconnected functional modules, including metabolic reprogramming, elevation of the apoptotic threshold, adjustment of the reactive oxygen species setpoint, and mitophagy-mediated mitochondrial quality control. Polysaccharides and polysaccharide-based systems may represent promising candidates for modulating mitochondria-associated dysfunctions because of their structural diversity, biological activity, and generally favorable biocompatibility in specific experimental settings.

Poly (ADP-ribose) polymerase (PARP) inhibitors demonstrate efficacy in breast cancer patients harboring pathogenic BRCA1/2 mutations. However, certain BRCA1 single nucleotide polymorphisms may alter protein function without complete loss of activity. This study investigates whether specific heterozygous BRCA1 single nucleotide polymorphisms within the central functional region of BRCA1 affect cellular sensitivity to PARP inhibition and explores the underlying transcriptomic mechanisms.

Oxidative stress, resulting from the disruption of redox homeostasis, is increasingly recognized as a central driver of gastric cancer pathogenesis and a critical determinant of cell fate. An imbalance between reactive oxygen species (ROS) production and cellular antioxidant defenses leads to oxidative stress, which may ultimately result in cellular oxidative death. Helicobacter pylori (H. pylori), through its virulence factors, induces a vicious cycle of oxidative stress and inflammation that collectively remodels the tumor microenvironment. Gastric cancer is molecularly heterogeneous, and ROS demonstrate profound context dependency across these different subtypes, with distinct mechanisms governing ROS generation, antioxidant defense, and redox-regulated cell death. Importantly, ROS orchestrate a diverse repertoire of cell death modalities in gastric cancer, including ferroptosis, apoptosis, necroptosis, cuproptosis, paraptosis, pyroptosis, and oxeiptosis via a regulatory network involving key molecules such as GPX4, SLC7A11, NRF2, and caspases. In-depth research into the mechanisms of cell death holds promise for developing preventive and therapeutic agents. This review summarizes the mechanisms of ROS‑regulated cell death and explores various therapeutic strategies, including the combined use of small‑molecule compounds and emerging nanomaterial‑based approaches, alongside conventional chemotherapy, immunotherapy, and radiotherapy, to target oxidative stress. It also highlights recent advances, opportunities, and challenges in translating these strategies into gastric cancer therapy. In conclusion, this review offers a mechanistically grounded framework for developing redox-targeted precision therapies in gastric cancer.

There is limited data on immune checkpoint inhibitor (ICI) use in patients with non-small cell lung cancer (NSCLC) and known pericardial effusions.

As cancer incidence rises in Asian countries, chemotherapy remains central to treatment amid rapid population aging and declining fertility in most of them. These trends underscore concern over long-term reproductive health, as chemotherapy-induced ovarian toxicity and premature ovarian insufficiency (POI) emerge as major late effects with unclear population-specific susceptibility. This review examines chemotherapy-induced ovarian damage via the PI3K-AKT-FOXO3 signaling axis, a key regulator of follicular quiescence, stress responses, and ovarian longevity. Evidence was synthesized from human studies, experimental models, and mechanistic investigations to develop this population-specific conceptual framework. Chemotherapy initiates DNA damage and oxidative stress, which subsequently activate interconnected pathways involving mitochondrial dysfunction, dysregulated autophagy, apoptosis, ferroptosis, inflammatory signaling, and dysregulation of the PI3K-AKT-FOXO3 axis, ultimately accelerating follicular activation and depletion. A distinctive contribution of this review is the integration of longevity-associated genetic susceptibility with ovarian vulnerability, highlighting evidence suggesting that certain FOXO3 and PI3K-AKT pathway variants, reported to be more prevalent in several Asian populations, may influence susceptibility to chemotherapy-induced ovarian injury. This review proposes a two-hit hypothesis as a conceptual framework integrating currently available molecular, experimental, and population-based evidence while acknowledging that direct clinical validation remains limited. Within this framework, longevity-associated genetic predisposition affecting the PI3K-AKT-FOXO3 axis constitutes the first hit, whereas chemotherapy-induced cellular stress represents the second hit, together accelerating follicular burnout and increasing the risk of POI. This framework supports future evaluation of genotype-informed risk stratification, individualized fertility preservation strategies, and prospective validation in Asian cancer cohorts, with the ultimate goal of informing ethnicity-specific fertility preservation strategies and optimized chemotherapy protocols.

Platinum anticancer drugs tend to target DNA whereas certain ruthenium and osmium organometallic compounds, including those with known anticancer activity, preferentially bind histone proteins in chromatin. We earlier found that Ru/Os arene 2-pyridinecarbothioamide antitumor agents display unique or partially overlapping profiles of histone protein binding in the nucleosome compared to Ru arene phosphaadamantane antimetastasis drugs, but the basis for this difference is unclear. Here, we structurally characterized the nucleosome binding effects of arene ligand substitutions and carried out a multiscale simulation analysis, which reveals that the interplay between metal cation and non-leaving ligand identity dictates adduct stability and whether complexes target electronegative surface patches, internal crevices, or both. We show that the nucleosome superhelical crevice acts as a small molecule selectivity filter and that multi-site binding profiles can be expanded or reduced through defined ligand substitutions, which modulate dynamic and steric attributes. Our findings suggest new avenues for rationally developing Ru/Os organometallics that could help expand the scope of chromatin-targeting therapeutics.

Immune checkpoint inhibitor (ICI) therapy for colorectal cancer (CRC) can be accompanied by endocrine adverse events, yet the comparative risk across commonly used regimens remains unclear. We therefore conducted a network meta-analysis of randomized controlled trials in CRC published up to November 22, 2025, estimating risk ratios (RRs) with 95% confidence intervals (CIs) and assessing risk of bias. Six RCTs were included. Relative to conventional therapy, ICI-based regimens were associated with a higher thyroid-related toxicity burden. Pembrolizumab and ICI+tyrosine kinase inhibitor (TKI) significantly increased the risk of hypothyroidism, whereas hyperthyroidism was significantly higher with ICI+TKI and ICI plus chemotherapy plus an anti-angiogenic antibody (ICI+Chem+Antiangio-Ab). Grade 1-2 adverse events were consistently increased across ICI-based treatments. For thyroiditis, diabetes mellitus, adrenal insufficiency, and grade 3-4 adverse events, effect estimates were imprecise with wide 95% CIs; nevertheless, SUCRA rankings tended to place ICI+TKI toward the higher-risk end for thyroiditis and diabetes. These findings indicate that ICI-containing strategies in CRC increase risks of endocrine adverse events-particularly for thyroid dysfunction-supporting the need for proactive endocrine monitoring and standardized management, while highlighting the limited precision of current evidence for rarer endpoints and severe toxicity.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. Immune checkpoint inhibitor (ICI) monotherapy has shown limited efficacy in PDAC, whereas the potential clinical value of first-line ICI-based combination regimens remains unclear. Through a systematic review and meta-analysis, this study aimed to evaluate the efficacy and safety of first-line ICI-based combination regimens in advanced PDAC.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapeutics yet frequently induce renal injury and multi-organ immune-related adverse events (irAEs) that present substantial clinical management challenges. Critical evidence gaps persist regarding dynamic immune microenvironment interactions and optimal organ-protective strategies.

Objectives: Venetoclax (VEN) is approved for acute myeloid leukemia (AML) in association with azacitidine, in a 28-day schedule at a fixed dosage, which requires reduction if azoles are co-administered. The present study aims to evaluate VEN therapeutic drug monitoring (TDM) in a real-word setting, where the VEN schedule is frequently reduced, investigating: (i) the posaconazole impact, and (ii) whether VEN exposure correlates with safety and efficacy. Methods: We analyzed data from 43 AML patients treated with different VEN-containing regimens, for whom a near-trough VEN plasma concentration (Cmin) was determined at different timepoints (days 5-8-11-15-22-29) across different cycles (163 cycles, 290 determinations). The posaconazole impact was explored in the whole study population, while safety and efficacy were investigated only in patients treated with azacitidine-VEN, respectively in the safety (35 patients) and in the efficacy subset (29 patients at their first cycle). VEN exposure was expressed through multiple parameters, taking into account both VEN concentrations and the days of VEN administration. Results: Posaconazole was used in 40.5% of cycles and, despite dose adjustment, was associated with: (i) greater interpatient variability, (ii) higher VEN concentrations, (iii) delayed elimination, (iv) accumulation along the cycle, and (v) the need for VEN-dosage change. In the safety subset, VEN exposure correlated with neutropenia and its duration, Granulocyte Colony-Stimulating Factor requirement, platelet transfusions, cycle duration, and infections. Finally, no correlation was found between VEN exposure and response in the efficacy subset. Conclusion: VEN TDM appears valuable in clinical practice to reduce toxicity, especially in patients receiving posaconazole, where VEN exposure remains highly unpredictable.

Proliferating Cell Nuclear Antigen (PCNA) is a core protein in DNA replication and repair. Its functional dysregulation drives tumorigenesis and therapeutic resistance, making it a critical anticancer target. However, the fundamental conflict between PCNA's indispensable "guardian" function in normal cells and its hijacked "accomplice" role in cancer cells constitutes the central challenge for targeted intervention: how to eradicate tumors while avoiding severe toxicity to normal tissues. This review aims to systematically review the latest advances and translational dilemmas in the field of PCNA-targeted therapy. It outlines various intervention strategies, including small-molecule inhibitors, proteolysis-targeting chimeras, post-translational modification interference, and synthetic lethality approaches, analyzing their potential and limitations in preclinical research. The review focuses on dissecting key bottlenecks hindering clinical translation, such as the selectivity dilemma, delivery barriers, and resistance evolution. Concurrently, it critically examines how cross-disciplinary technologies-including artificial intelligence, spatiotemporal regulation, and synthetic biology-offer novel ideas to address these bottlenecks, while clarifying that most remain in early exploratory stages. By synthesizing progress, challenges, and future directions, this article provides a framework to inform the development of highly selective and translatable PCNA-based anticancer strategies.

Lung cancer in individuals who have never smoked (LCINS) represents a clinically and biologically distinct subset of non-small cell lung cancer, driven predominantly by oncogenic alterations rather than tobacco-related mutagenesis. This review aims to summarize current and emerging targeted and immune-based therapeutic strategies in LCINS individuals. These patients present a molecular profile that differs substantially from tobacco-associated disease and has direct consequences for treatment selection. Evidence published over the past five years has clarified how these molecular features shape treatment response and resistance in this setting. Particular attention is given to tumors with alterations in epidermal growth factor receptor, anaplastic lymphoma kinase, c-ros oncogene 1, rearranged during transfection, Mesenchymal-Epithelial Transition (MET) exon 14 skipping mutation, human epidermal growth factor receptor 2, valine-to-glutamic acid substitution at codon 600 of the BRAF gene (BRAF V600E), and neurotrophic tyrosine receptor kinase, which together comprise the dominant driver landscape in never-smoker lung cancer. Although third-generation tyrosine kinase inhibitors have markedly improved response rates in several of these subgroups, long-term disease control is frequently compromised by acquired resistance, and heterogeneous drug exposure, particularly in the central nervous system. By contrast, immune checkpoint inhibitors have yielded limited benefit, in keeping with the low mutational burden and generally low baseline immune activation observed in most LCINS tumors. As a result, alternative approaches such as antibody-drug conjugates, bispecific antibodies, and adoptive cellular therapies are being evaluated to address gaps left by existing treatments.

Despite the use of targeted and/or immune-based therapeutic approaches, mortality rates among melanoma patients are high, mainly due to drug-induced resistance mechanisms. In parallel, alterations of epigenetic mechanisms (e.g., deregulated patterns of DNA methylation, aberrant histone modifications and abnormal expression levels of non-coding RNAs [ncRNAs]) have been associated not only with the pathophysiology of melanoma but also with the resistance against various immunotherapeutic drugs. In this review article, we discuss the involvement of different types of epigenetic mechanisms in melanoma progression. In addition, we report on melanoma's immune environment and immunosuppressive mechanisms while we highlight the role of immune checkpoint inhibitors (ICIs) as an anti-melanoma therapeutic approach. Moreover, we describe the underlying mechanism(s) by which deregulated epigenetic patterns promote drug resistance against ICIs and how epigenetic drugs (utilized either alone or in combination with various ICIs) can reverse immune resistance. Furthermore, we discuss the major limitations and future directions towards clinical translation of epigenetic drugs, mainly in combination with ICIs. Finally, we state the potential use of emerging technologies (e.g., single-cell transcriptomics and spatial transcriptomics), along with epigenetic priming for improvement of clinical implementation and therapeutic outcomes in melanoma management.